CN114106252A - Color-developing embolism microsphere and preparation method thereof - Google Patents
Color-developing embolism microsphere and preparation method thereof Download PDFInfo
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Abstract
A chromogenic embolism microsphere and a preparation method thereof, belonging to the technical field of embolism microspheres. The preparation method of the chromogenic embolic microsphere comprises the following steps: adding an aqueous phase into the oil phase to form a water-in-oil reversed phase suspension polymerization system, and heating to 70-85 ℃ to perform reversed phase suspension polymerization; at least one of the aqueous phase and the oil phase has a pH of no greater than 6; wherein the water phase contains water-soluble monomer, initiator and high molecular monomer aqueous solution; the water-soluble monomer contains at least one of a sulfonic acid group and a carboxylic acid group, and contains a polymerizable double bond. The preparation method can prepare the embolic microsphere in a yellow color system without introducing reactive dye for dyeing.
Description
Technical Field
The application relates to the technical field of embolism microspheres, in particular to a chromogenic embolism microsphere and a preparation method thereof.
Background
At present, the embolism microsphere is mostly used for embolizing various blood-rich tumors, and the embolism microsphere can also be used for embolization treatment of hysteromyoma, urinary tract obstruction caused by prostatic hyperplasia, hemorrhagic diseases, hyperthyroidism and other diseases.
At present, the partially commercialized embolization microspheres are colorless transparent spheres, and the colorless embolization microspheres are difficult to observe by doctors in the preparation process of the operation and are inconvenient to operate. To address this problem, the embolic microspheres are typically dyed with a reactive dye. In the prior art, the embolism microsphere is dyed by active blue, and although the dye is combined with a functional group on the embolism microsphere in a covalent bond form, the dye has no toxic or side effect on a human body clinically, the active blue residue still exists, and the requirement on the limit of the active blue residue is extremely low; the dyeing step is complex, the temperature is high, the energy consumption is high, and a large amount of waste water is generated to cause environmental pollution.
Disclosure of Invention
The embodiment of the application provides a chromogenic embolism microsphere and a preparation method thereof, the preparation method can prepare the chromogenic embolism microsphere in a yellow system, and reactive dye is not required to be introduced to dye the microsphere.
The embodiment of the application is realized as follows:
in a first aspect, an embodiment of the present application provides a method for preparing a chromogenic embolic microsphere, comprising:
adding an aqueous phase into the oil phase to form a water-in-oil reversed phase suspension polymerization system, and heating to 70-85 ℃ to perform reversed phase suspension polymerization; at least one of the aqueous phase and the oil phase has a pH of no greater than 6;
wherein the water phase contains water-soluble monomer, initiator and high molecular monomer aqueous solution;
the water-soluble monomer contains at least one of a sulfonic acid group and a carboxylic acid group, and contains a polymerizable double bond.
In a second aspect, embodiments of the present application provide a chromogenic embolic microsphere, which is prepared by the method of the first aspect, and the chromogenic embolic microsphere is a yellow system.
The embodiment of the application has at least the following beneficial effects:
in the preparation method of the color-developing embolism microsphere, the water phase contains a water-soluble monomer, an initiator and a high molecular monomer aqueous solution, the water phase is added into the oil phase, reversed phase suspension polymerization reaction is carried out at the temperature of 70-85 ℃, under the action of the initiator, the water-soluble monomer containing at least one of a sulfonic acid group and a carboxylic acid group and containing polymerizable double bonds is subjected to cross-linking reaction to obtain a polymer with an ionic functional group, and the high molecular monomer is subjected to polymerization reaction to obtain a cross-linking structure and is subjected to cross-linking and winding blending with the polymer cross-linking structure with the ionic functional group in the polymerization process to form the embolism microsphere. The inventor of the application discovers in research that the pH value of at least one of the oil phase and the water phase in the embodiment of the application is not more than 6, and when the reaction temperature is 70-85 ℃, the finally formed embolism microsphere is in a yellow system, the color is obvious by naked eye observation, the operation in the operation process can be facilitated, and the microsphere is not required to be dyed by introducing reactive dye.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained from the drawings without inventive effort.
FIG. 1 is a flow chart of a process for preparing a chromogenic embolic microsphere in accordance with an embodiment of the present application;
FIG. 2 is a photograph of embolization microspheres from examples 1-2 of the present application and a control sample (8-Spheres, 300-500 μm, Calkyamus Risheng biomedical science and technology, Inc., Suzhou);
FIG. 3 is a photograph of embolized microspheres according to examples 3-9 of the present application and a control sample;
FIG. 4 is a photograph of embolized microspheres from comparative examples 1 to 4 of the present application and a control sample.
Detailed Description
Embodiments of the present application will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present application and should not be construed as limiting the scope of the present application. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following is a detailed description of the chromogenic embolic microsphere and the preparation method thereof in the embodiments of the present application:
referring to fig. 1, an embodiment of the present application provides a method for preparing a chromogenic embolic microsphere, comprising:
adding an aqueous phase into the oil phase to form a water-in-oil reversed phase suspension polymerization system, and heating to 70-85 ℃ to perform reversed phase suspension polymerization; at least one of the aqueous phase and the oil phase has a pH of no greater than 6.
Wherein the water phase contains water-soluble monomer, initiator and high molecular monomer aqueous solution;
the water-soluble monomer contains at least one of a sulfonic acid group and a carboxylic acid group, and contains a polymerizable double bond.
In the preparation method of the color-developing embolism microsphere, the water phase contains a water-soluble monomer, an initiator and a high molecular monomer aqueous solution, the water phase is added into the oil phase, reversed phase suspension polymerization reaction is carried out at the temperature of 70-85 ℃, under the action of the initiator, the water-soluble monomer containing at least one of a sulfonic acid group and a carboxylic acid group and containing polymerizable double bonds is subjected to cross-linking reaction to obtain a polymer with an ionic functional group, and the high molecular monomer is subjected to polymerization reaction to obtain a cross-linking structure and is subjected to cross-linking and winding blending with the polymer cross-linking structure with the ionic functional group in the polymerization process to form the embolism microsphere.
Wherein the rate of addition of the aqueous phase to the oil phase affects the particle size of the finally formed embolized microspheres, illustratively by dropwise addition. In addition, the addition of the aqueous phase to the oil phase is carried out under stirring conditions.
Alternatively, the stirring speed is 200 to 700rpm, for example, any one or a range between 200rpm, 300rpm, 400rpm, 500rpm, 600rpm and 700rpm, with stirring, during the reverse phase suspension polymerization.
Optionally, the reverse phase suspension polymerization reaction is carried out for 12-18 h, such as any one of 12h, 14h, 16h and 18h or a range between any two.
The inventor of the application discovers in research that the pH value of at least one of the oil phase and the water phase in the embodiment of the application is not more than 6, and when the reaction temperature is 70-85 ℃, the finally formed embolism microsphere is in a yellow system, the color is obvious by naked eye observation, the operation in the operation process can be convenient, and further dyeing is not needed. It should be noted that, the inventors of the present application found in their research that if the reaction temperature is greater than 85 ℃, the embolization microspheres cannot be formed; when the pH of at least one of the oil phase and the aqueous phase of the examples herein is not greater than 6 and the reaction temperature is less than 70 ℃, the finally formed embolic microspheres are colorless.
Alternatively, in the present embodiment, the temperature at which the reversed-phase suspension polymerization is carried out is any one of 70 ℃, 73 ℃, 75 ℃, 78 ℃, 80 ℃, 83 ℃ and 85 ℃ or a range between any two of them.
In addition, the fact that the pH of at least one of the oil phase and the aqueous phase is not more than 6 means that the pH of the oil phase is not more than 6, the pH of the aqueous phase is not more than 6, or the pH of both the oil phase and the aqueous phase is not more than 6.
Illustratively, at least one of the aqueous phase and the oil phase has a pH of 1 to 6, e.g., a pH of any one of 1, 2, 3, 4, 5, and 6 or a range between any two.
In some embodiments, at least one of the aqueous phase and the oil phase contains a pH adjusting agent such that the pH of the corresponding phase is no greater than 6. That is, the pH of the aqueous phase can be made not more than 6 by adding a pH adjuster to the aqueous phase, and the pH of the oil phase can be made not more than 6 by adding a pH adjuster to the oil phase.
Illustratively, the pH adjusting agent includes at least one of hydrochloric acid, nitric acid, sulfuric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and ammonia water.
In some embodiments, the water soluble monomer comprises at least one of sodium acrylate, sodium methacrylate, sodium 2-acrylamido-2-methylpropanesulfonate.
Wherein, both the sodium acrylate and the sodium methacrylate simultaneously contain carboxylic acid groups and polymerizable double bonds, and the 2-acrylamide-2-methyl sodium propane sulfonate simultaneously contains sulfonic acid groups and polymerizable double bonds.
In some embodiments, the step of preparing the aqueous phase comprises: dissolving a water-soluble high polymer material and a water-soluble cross-linking agent in water, reacting in the water to obtain a high polymer monomer aqueous solution, and then mixing a water-soluble monomer, an initiator and the high polymer monomer aqueous solution. The water-soluble cross-linking agent contains at least one polymerizable double bond and at least one aldehyde, acetal or hemiacetal group; the water-soluble polymer material contains a plurality of hydroxyl groups.
The water-soluble high molecular material and the water-soluble cross-linking agent can be dissolved in water, the water-soluble high molecular material containing hydroxyl and the water-soluble cross-linking agent containing at least one polymerizable double bond and at least one aldehyde group, acetal group or hemiacetal group can perform cross-linking reaction in the water to obtain a high molecular monomer, and finally obtain a high molecular monomer aqueous solution.
Optionally, the water-soluble polymer material includes at least one of polyvinyl alcohol and polysaccharide. Illustratively, the polysaccharide includes at least one of sodium alginate and sodium hyaluronate. The polyvinyl alcohol, the sodium alginate and the sodium hyaluronate all contain a large amount of hydroxyl groups, and can generate crosslinking reaction with a water-soluble crosslinking agent within a reaction temperature range.
Illustratively, the water-soluble cross-linking agent comprises at least one of N- (2, 2-dimethoxy) -2-methacrylamide and N- (1-hydroxy-2, 2-dimethoxyethyl) -2-acrylamide, wherein the water-soluble cross-linking agent contains at least one polymerizable double bond at one end and at least one aldehyde, acetal or hemiacetal group at the other end.
When the pH value of the aqueous phase is not more than 6, illustratively, the pH adjuster is dissolved in water to obtain a pH adjuster solution, and then the pH adjuster solution is mixed with the aqueous polymer monomer solution, the water-soluble monomer, and the initiator to obtain the aqueous phase.
Optionally, the initiator comprises at least one of persulfate, hydrogen peroxide and water soluble azo type initiators. Wherein the persulfate can be at least one of potassium persulfate and ammonium persulfate.
The water-soluble polymer material is dissolved in water at a temperature of 90-100 ℃, and in the specific operation, the water-soluble polymer material is added into water, the temperature is raised to 90-100 ℃, then the water-soluble polymer material is stirred and dissolved to form a uniform solution, and then the water-soluble cross-linking agent is added and stirred uniformly to obtain a polymer monomer aqueous solution.
Illustratively, the mass of the water-soluble polymer material in the aqueous polymer monomer solution is 10 to 20% of the mass of water, for example, 10%, 12%, 14%, 16%, 18%, and 20% or a range between any two of them, based on the water in the aqueous polymer monomer solution; the mass of the water-soluble crosslinking agent is 0.1-1% of the mass of water, and is, for example, in the range of 0.1%, 0.3%, 0.5%, 0.7%, 0.9%, and 1% or in the range between any two of them.
Illustratively, the mass of the aqueous solution of the polymeric monomer in the aqueous phase is 5 to 15% of the mass of water, for example, 5%, 8%, 10%, 12%, and 15% or a range between any two of them, based on the water in the pH adjuster solution.
When the content of the water-soluble polymer material in the water phase is too low, the formed embolism microsphere has smaller size and lower yield; when the content of the water-soluble polymer material in the water phase is too high, the viscosity of the water phase is higher, the dispersion degree in the oil phase is reduced, and the agglomeration of the embolism microspheres is easily caused.
In addition, when the content of the cross-linking agent in the water phase is too low, the strength of the embolism microsphere is easy to be lower; when the content of the cross-linking agent in the aqueous phase is too high, the elasticity of the embolization microspheres is easily low.
The mass of the water-soluble monomer in the aqueous phase is 2-7% of the water based on the water in the pH regulator solution, for example, any one of 2%, 3%, 4%, 5%, 6% and 7%, or a range between any two of them; the mass of the initiator in the aqueous phase is 0.5-7% of the water, for example, 0.5%, 2%, 3%, 4%, 5%, 6% and 7% or a range between any two.
When the content of the water-soluble monomer is lower, the drug loading capacity of the embolism microsphere is easily influenced; when the content of the water-soluble monomer is high, it is liable that the compressive elasticity of the embolization microspheres is lowered.
In some embodiments, the aqueous phase contains a second catalyst, the second catalyst being an acid-based catalyst comprising at least one of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and p-toluenesulfonic acid. For example, the second catalyst may be added to the aqueous polymer monomer solution and then mixed with the water-soluble monomer and the initiator.
The water phase contains the second catalyst, so that the cross-linking reaction of the water-soluble high polymer material and the cross-linking agent can be accelerated in the reversed-phase suspension polymerization reaction process.
In some embodiments, a first catalyst may be further added before or during the reverse phase suspension polymerization, the first catalyst comprising an organic amine, the organic amine comprising at least one of tetramethylethylenediamine, N-ethylethylenediamine, and ethylenediamine.
By adding the first catalyst, the crosslinking reaction of the water-soluble polymer material and the crosslinking agent and the polymerization reaction of the water-soluble monomer can be accelerated. During the specific operation, the water phase is added into the oil phase to form a water-in-oil reversed phase suspension polymerization system, then the temperature is raised to 70-85 ℃, and the first catalyst is added. Or adding an aqueous phase into the oil phase to form a water-in-oil reversed phase suspension polymerization system, adding a first catalyst, and then heating to 70-85 ℃ to perform reversed phase suspension polymerization.
In some embodiments, the step of preparing the oil phase comprises: dissolving an oil-soluble dispersant into an oil phase solvent at the temperature of 30-50 ℃ to obtain an oil phase, wherein the oil-soluble dispersant is cellulose containing butyryl.
Optionally, the oil soluble dispersant comprises cellulose acetate butyrate, span, preferably cellulose acetate butyrate. Optionally, the oil phase solvent comprises one or more of liquid alkanes with more than 8 carbon atoms, liquid ester solvents, ethyl acetate and butyl acetate, preferably butyl acetate.
The embodiment of the application also provides a chromogenic embolism microsphere, which is prepared by the preparation method of the chromogenic embolism microsphere in the embodiment of the application, and the chromogenic embolism microsphere is a yellow system.
The chromogenic embolism microsphere prepared by the embodiment of the application is in a yellow system, and the color is obvious by visual observation, so that the operation in the operation process can be facilitated. The yellow color system in the present embodiment may be light yellow, orange yellow, or the like.
Illustratively, the chroma is 0.7-1.6, such as any one or a range between any two of 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6.
The chromogenic embolic microspheres of the present application and methods for making the same are described in further detail below with reference to the examples.
Example 1
The embodiment provides a preparation method of a chromogenic embolic microsphere, which comprises the following steps:
(1) adding 18.00g of polyvinyl alcohol into 150.00g of water, heating to 95 ℃, stirring for dissolution, then adding 0.25g N- (2, 2-dimethoxy) -2-methacrylamide, stirring uniformly, adding 12.5g of hydrochloric acid, stirring for 12 hours, and then adding sodium hydroxide for neutralization to neutrality to obtain a high molecular monomer aqueous solution.
(2) Mixing 7.00g of sodium acrylate, 1.00g of potassium persulfate and the aqueous solution of the polymer monomer prepared in the step (1), and adding an aqueous hydrochloric acid solution to adjust the pH value of the solution to obtain an aqueous phase with the pH value of 3.5.
(3) 20.00g of cellulose acetate butyrate was dissolved in 1200.00g of butyl acetate, and the solution was stirred at a temperature of 40 ℃ to obtain an oil phase.
(4) And (2) dropwise adding the water phase into the oil phase under the stirring condition to form a water-in-oil reversed-phase suspension polymerization system, heating the reversed-phase suspension polymerization system to 75 ℃ after dropwise adding, then adding 8.00g of tetramethyldiamine, stopping heating and stirring after reacting for 15h, standing, separating the oil phase after layering, collecting the embolism microspheres, and repeatedly cleaning.
Example 2
The embodiment provides a preparation method of a chromogenic embolic microsphere, which comprises the following steps:
(1) adding 18.00g of sodium hyaluronate into 150.00g of water, heating to 90 ℃, stirring for dissolving, then adding 0.25g of N- (2, 2-dimethoxy) -2-methacrylamide, stirring uniformly, adding 12.50g of sulfuric acid, stirring for 12 hours, and then adding sodium hydroxide for neutralization to neutrality to obtain the polymer monomer aqueous solution.
(2) Mixing 7.00g of sodium acrylate, 1.00g of potassium persulfate and the aqueous solution of the polymer monomer prepared in the step (1), adding an aqueous hydrochloric acid solution to adjust the pH value of the solution, and obtaining an aqueous phase with the pH value of 2.5.
(3) 20.00g of cellulose acetate butyrate was dissolved in 1200.00g of ethyl acetate, and the solution was stirred at 35 ℃ to obtain an oil phase.
(4) And (2) dropwise adding the water phase into the oil phase under the stirring condition to form a water-in-oil reversed-phase suspension polymerization system, heating the reversed-phase suspension polymerization system to 85 ℃ after dropwise adding, then adding 8.00g of tetramethyldiamine, stopping heating and stirring after reacting for 15h, standing, separating the oil phase after layering, collecting the embolism microspheres, and repeatedly cleaning.
Examples 3 to 8
Examples 3 to 8 each provide a method for producing a colored embolization microsphere, which is different from example 1 only in that the pH of the aqueous phase in step (2) in examples 3 to 8 is different from example 1. Wherein the pH of the aqueous phase in examples 3 to 8 was 1, 2, 3, 4, 5 and 6, respectively.
Example 9
The embodiment provides a preparation method of a chromogenic embolic microsphere, which comprises the following steps:
(1) adding 18.00g of polyvinyl alcohol into 150.00g of water, heating to 95 ℃, stirring for dissolution, then adding 0.25g of N- (2, 2-dimethoxy) -2-methacrylamide, stirring uniformly, adding 12.50g of hydrochloric acid, stirring for 12 hours, and then adding sodium hydroxide for neutralization to neutrality to obtain a high molecular monomer aqueous solution.
(2) 7.00g of sodium acrylate, 1.00g of potassium persulfate and the aqueous polymer monomer solution obtained in step (1) were mixed to obtain an aqueous phase.
(3) 20.00g of cellulose acetate butyrate was dissolved in 1200.00g of butyl acetate, and the solution was dissolved at 40 ℃ with stirring, and then an aqueous hydrochloric acid solution was added to adjust the pH of the solution to obtain an oil phase having a pH of 4.
(4) And (2) dropwise adding the water phase into the oil phase under the stirring condition to form a water-in-oil reversed-phase suspension polymerization system, heating the reversed-phase suspension polymerization system to 75 ℃ after dropwise adding, then adding 8.00g of tetramethyldiamine, stopping heating and stirring after reacting for 15h, standing, separating the oil phase after layering, collecting the embolism microspheres, and repeatedly cleaning.
Comparative example 1
Comparative example 1 provides a method for preparing embolic microspheres, which is different from example 1 only in that hydrochloric acid in step (2) of example 1 is replaced with sodium bicarbonate, and the pH of the aqueous phase of step (2) of comparative example 1 is different from example 1, wherein the pH of the aqueous phase of comparative example 1 is 7.
Comparative example 2
Comparative example 2 provides a method for preparing embolic microspheres, which is different from example 1 only in that hydrochloric acid in step (2) of example 1 is replaced with potassium hydroxide, and the pH of the aqueous phase in step (2) of comparative example 1 is different from example 1, wherein the pH of the aqueous phase in comparative example 1 is 8.
Comparative example 3
Comparative example 3 provides a method for preparing embolic microspheres, which is different from example 1 only in that the heating temperature in step (4) in example 1 is replaced with 65 ℃.
Comparative example 4
Comparative example 4 provides a method for preparing embolic microspheres, which is different from example 1 only in that the heating temperature in step (4) in example 1 is replaced with 55 ℃.
Test examples
(1) The embolizing microspheres from examples 1-9 and comparative examples 1-4 were observed manually and the color results observed are reported in table 1. The photographs of the embolization microspheres of examples 1-2 and the control sample (8-Spheres, 300-500 μm, henrykia ni bio-medical science and technology ltd, su) are shown in fig. 2, and fig. 2 shows the embolization microspheres from left to right corresponding to examples 1, 2 and the control sample, respectively; photographs of the embolization microspheres of examples 3 to 9 and the control sample are shown in fig. 3, and fig. 3 corresponds to the embolization microspheres of examples 3, 4, 5, 6, 7, 8, 9 and the control sample, respectively, from left to right; photographs of the plugged microspheres of comparative examples 1 to 4 and the control sample are shown in fig. 4, and fig. 4 corresponds to the plugged microspheres of comparative example 1, comparative example 2, comparative example 3, comparative example 4 and the control sample, respectively, from left to right.
(2) The embolization microspheres prepared in examples 1 to 9 and comparative examples 1 to 4 were subjected to color difference detection using a 3NH color difference meter (NH310), and the specific test method was as follows: a colorless and transparent control sample (8-Spheres, 300-500 μm, Li Bio-medicine science and technology, constant Riga, Suzhou) was added into the sample cell for detection, and then the samples in the examples and comparative examples were added into the sample cell for detection, and the results are recorded in Table 1. Note that the color difference (Δ a) in the table is (sample a value in example or comparative example) - (a value in control sample).
TABLE 1 color and color difference of embolizing microspheres
From the results in table 1, it can be seen that the color of the embolization microspheres prepared by the preparation method of the example can be observed by naked eyes, while the color of the embolization microspheres prepared by the comparative examples 1 to 4 is colorless, which indicates that the color of the embolization microspheres can be obtained by controlling the pH value of the water phase of the example to be not more than 6 and controlling the reaction temperature to be 70 to 85 ℃.
The foregoing is illustrative of the present application and is not to be construed as limiting thereof, as numerous modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A method for preparing a chromogenic embolic microsphere, comprising:
adding an aqueous phase into the oil phase to form a water-in-oil reversed phase suspension polymerization system, and heating to 70-85 ℃ to perform reversed phase suspension polymerization; at least one of the aqueous phase and the oil phase has a pH of no greater than 6;
wherein the water phase contains a water-soluble monomer, an initiator and a high molecular monomer aqueous solution;
the water-soluble monomer contains at least one of a sulfonic acid group and a carboxylic acid group, and contains a polymerizable double bond.
2. The method for preparing the chromogenic embolic microsphere according to claim 1, wherein at least one of the aqueous phase and the oil phase has a pH of 1 to 6.
3. The method of preparing a colored embolic microsphere of claim 1, wherein at least one of the aqueous phase and the oil phase contains a pH adjusting agent comprising at least one of hydrochloric acid, nitric acid, sulfuric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and ammonia such that the pH of the corresponding phase is not greater than 6.
4. The method for preparing the chromogenic embolic microsphere according to any one of claims 1 to 3, wherein the water-soluble monomer comprises at least one of sodium acrylate, sodium methacrylate and sodium 2-acrylamido-2-methylpropanesulfonate.
5. The method for preparing color-developing embolism microsphere according to any one of claims 1 to 3, wherein a first catalyst is further added before or during the reverse phase suspension polymerization reaction, wherein the first catalyst comprises organic amine, and the organic amine comprises at least one of tetramethylethylenediamine, N-ethylethylenediamine and ethylenediamine.
6. The method for preparing the color-developing embolism microsphere according to any one of claims 1 to 3, wherein the aqueous phase contains a second catalyst, and the second catalyst is an acid catalyst.
7. The method for preparing chromogenic embolic microspheres according to any one of claims 1 to 3, wherein the step of preparing the aqueous phase comprises: reacting a water-soluble polymer material with a water-soluble cross-linking agent in water to obtain a polymer monomer aqueous solution, and then mixing the water-soluble monomer, the initiator and the polymer monomer aqueous solution; the water-soluble cross-linking agent contains at least one polymerizable double bond and at least one aldehyde, acetal or hemiacetal group; the water-soluble polymer material contains a plurality of hydroxyl groups.
8. The method for preparing the chromogenic embolic microsphere according to claim 7, wherein the water-soluble polymer material comprises at least one of polyvinyl alcohol and polysaccharide.
9. The preparation method of the chromogenic embolic microsphere according to any one of claims 1 to 3, wherein the preparation step of the oil phase comprises: dissolving an oil-soluble dispersant into an oil phase solvent at the temperature of 30-50 ℃ to obtain the oil phase, wherein the oil-soluble dispersant is cellulose containing butyryl.
10. A chromogenic embolic microsphere, prepared by the method of any one of claims 1 to 9, wherein the chromogenic embolic microsphere is of a yellow color.
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